Despite advances in diagnosis and management, the clinical syndrome of heart failure remains a leading cause of hospitalization and death in developed countries with a worse five year prognosis than most cancers (Jhund P S, Macintyre K, Simpson C R, Lewsey J D, Stewart S, Redpath A, Chalmers J W, Capewell S, McMurray J J. Long-term trends in first hospitalization for heart failure and subsequent survival between 1986 and 2003: a population study of 5.1 million people. Circulation. 2009; 119:515-523; these and all other references cited herein are incorporated by reference for all purposes). Disparate mechanisms of cardiac stress invoke a common pathway of adaptive myocyte hypertrophy which progresses to impaired systolic function and dilated, thinned myocardium. Expression of several genes is known to differ reproducibly between normal adult myocardium and failing and hypertrophied myocardium. Some of these differentially expressed genes, such as cardiac muscle alpha-myosin heavy chain 6 (MYH6) and cardiac muscle beta-myosin heavy chain 7 (MYH7), comprise the contractile apparatus of the sarcomere. Others, such as sarcoplasmic reticulum calcium ATPase 2 (ATP2A2), phospholamban (PLN), and solute carrier family 2, facilitated glucose transporter member 4 (SLC2A4), are principally involved in myocardial calcium cycling and energetics (Feldman A M, Weinberg E O, Ray P E, Lorell B H. Selective changes in cardiac gene expression during compensated hypertrophy and the transition to cardiac decompensation in rats with chronic aortic banding. Circ Res. 1993; 73:184-192; Lyn D, Liu X, Bennett N A, Emmett N L. Gene expression profile in mouse myocardium after ischemia. Physiol Genomics. 2000; 2:93-100; Yue P, Long C S, Austin R, Chang K C, Simpson P C, Massie B M. Post-infarction heart failure in the rat is associated with distinct alterations in cardiac myocyte molecular phenotype. J Mol Cell Cardiol. 1998; 30:1615-1630; Rajabi M, Kassiotis C, Razeghi P, Taegtmeyer H. Return to the fetal gene program protects the stressed heart: a strong hypothesis. Heart Fail Rev. 2007; 12:331-343; Chien K R. Stress pathways and heart failure. Cell. 1999; 98:555-558; Hoshijima M, Chien K R. Mixed signals in heart failure: cancer rules. J Clin Invest. 2002; 109:849-855).
It has thus been proposed that myocardial adaptation involves myosin switch and a switch from fatty acid oxidation to glycolysis as the main metabolic pathway of the cardio myocyte. Similar differential gene expression has been observed in fetal myocardium, leading to a hypothesis that there is a coordinated gene program that overlaps between fetal and failing and hypertrophied myocardium 5. It is, however, unclear whether such changes represent a truly coordinated biological response mediated by common regulators.
The incomplete understanding of these shared genomic response pathways is largely due to statistical and computational limitations inherent to traditional differential expression experiments, in which the expression of a pre-defined set of genes is compared between two different phenotypes. These limitations have been compounded by small sample sizes in previous microarray experiments and have precluded prior unbiased genome-wide evaluation of this hypothesis.
Network based approaches can be used to identify patterns of shared gene expression, regulation, or protein interaction while limiting the number of statistical comparisons and thus the false discovery rate (Jeong H, Mason S P, Barabasi A L, Oltvai Z N. Lethality and centrality in protein networks. Nature. 2001; 411:41-42; Jeong H, Tombor B, Albert R, Oltvai Z N, Barabasi A L. The large-scale organization of metabolic networks. Nature. 2000; 407:651-654). Literature derived networks have been used to reveal potential targets for abrogation of restenotic atherosclerotic coronary artery disease and in doing so recapitulated targets of known therapeutic agents. Other investigators have used gene coexpression analysis to uncover pathways regulated by disease susceptibility genes (Chen Y, Zhu J, Lum P Y, Yang X, Pinto S, MacNeil D J, Zhang C, Lamb J, Edwards S, Sieberts S K, Leonardson A, Castellini L W, Wang S, Champy M F, Zhang B, Emilsson V, Doss S, Ghazalpour A, Horvath S, Drake T A, Lusis A J, Schadt E E. Variations in DNA elucidate molecular networks that cause disease. Nature. 2008; 452:429-435). Candidate causal gene relationships have subsequently been validated with high fidelity in transgenic and gene knock-down experiments (Yang X, Deignan J L, Qi H, Zhu J, Qian S, Zhong J, Torosyan G, Majid S, Falkard B, Kleinhanz R R, Karlsson J, Castellani L W, Mumick S, Wang K, Xie T, Coon M, Zhang C, Estrada-Smith D, Farber C R, Wang S S, van Nas A, Ghazalpour A, Zhang B, Macneil D J, Lamb J R, Dipple K M, Reitman M L, Mehrabian M, Lum P Y, Schadt E E, Lusis A J, Drake T A. Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks. Nat Genet. 2009; 41:415-423; Schadt E E. Molecular networks as sensors and drivers of common human diseases. Nature. 2009; 461:218-223).